Clinical Research
Cardiometabolic Risk
Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels: Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins

https://doi.org/10.1016/j.jacc.2012.08.986Get rights and content
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Objectives

The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy.

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling.

Methods

Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3.

Results

In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b).

Conclusions

In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.

Key Words

hypercholesterolemia
LDL-C
PCSK9

Abbreviations and Acronyms

AE
adverse event
ApoB
apolipoprotein B
CK
creatine kinase
HDL-C
high-density lipoprotein cholesterol
HeFH
heterozygous familial hypercholesterolemia
LDL-C
low-density lipoprotein cholesterol
LDL-R
low-density lipoprotein receptor
Lp(a)
lipoprotein (a)
PCSK9
proprotein convertase subtilisin/kexin type 9
QW
weekly
Q2W
every 2 weeks
Q4W
every 4 weeks

Cited by (0)

The studies reported in this manuscript were funded by Amgen, Thousand Oaks, California. Dr. Dias, Dr. Shaywitz, Dr. Wasserman, Mr. Colbert, Dr. Cooke, Ms. Crispino, Dr. Emery, Dr. Gibbs, Dr. Retter, Dr. Smirnakis, Dr. Smith, Dr. Stolman, and Mr. Uy are employees of and stockholders in Amgen. Dr. Gao was an Amgen employee and stockholder during the analysis of this study and development of the manuscript. Dr. Matson has no industry relationships to disclose. Dr. Stein has received consulting fees from Amgen, Adnexus Therapeutics, and Sanofi related to proprotein convertase subtilisin/kexin type 9 inhibitors, and his institution has received research funding related to proprotein convertase subtilisin/kexin type 9 clinical trials from Amgen, Sanofi, and Regeneron.